short term induction of ketosis in pkd

Conditions: ADPKD

Summary: recently, it has been shown that ketose-inducing dietary interventions slow disease progression in animal models of polycystic kidney disease (pkd), even when the state of ketosis is only induced for a short period of time. the present study aims to investigate the effects of short term ketosis on total kidney volume (tkv) (and other parameters) in 10 adpkd-patients with rapidly progressive disease.

recently, dietary models inducing ketosis have been shown to inhibit disease progression in animal models of pkd. those beneficial dietary models included time-restricted feeding (trf) without caloric reduction, ad libitum administered ketogenic diet (kd) and acute short-term fasting in mouse, rat and feline models of pkd. in a pkd rat model, trf without caloric reduction resulted in a strong inhibition of mtor signaling, proliferation and fibrosis in the affected kidneys. the adminstration of an ad libitum fed kd led to similar results. in rat, mouse and feline models of pkd, acute fasting led to a significant reduction of cyst volume. therefore, cystic cells seem to be metabolically inflexible and exhibit an altered metabolism characterized by increased glycolysis and, amongst others, defective fatty acid oxidation, similar to the warburg effect in cancer. (torres, kruger et al. 2019) while those beneficial observations were made in mouse, rat and feline models of pkd, the effects of a ketogenic diet in human adpkd patients have not been investigated yet, even though the adminstration of ketogenic diets is used as a treatment for epilepsy in children since the 1920s and fasting is one of the oldest medical procedures. therefore, the aim of the present study is to investigate the effects of a short-period ketonic state in 10 adpkd patients with fast progressive disease. 10 adpkd-patients (aged 18-60 years, ckd g 1-3a) will be enrolled after giving informed consent. these 10 subjects will go through four trial-related visits. during these visits, physical examinations will be performed, blood will be drawn, urine will be collected and ketone body measurements in breath, blood and urine will be carried out. each study visit includes an abdominal mri-scan. between visit 1 and visit 2, patients will eat their regular carbohydrate-rich diet. after visit 2, a ketonic state will be induced in those patients. patients can choose whether the ketonic state will be induced by acute fasting for 72 hours (under sufficient water consumption and salt substitution) or by eating a kd for 14 days. study visit 3 will take place within 72 hours after finishing the dietary intervention. after study visit 3, patients will restart eating their regular diet. study visit 4 will provide follow-up data 3-6 weeks after the dietary intervention. after study completion, the relative difference of tkv measured by mri-based volumetry of the kidneys immediately before and immediately after the ketonic state, will be compared to tkv growth/decline while eating a regular carbohydrate-rich diet. in general, patients are counselled in our outpatient department as part of "the german ad(h)pkd registry" (more than 700 patients enrolled). as from those patients, clinical data, laboratory data and imaging studies are present, identification and recruitment of patients with fast rapidly progressing disease will be facilitated. also, the investigators are closely liaised with the german self-help group pkdcure (pkd familiaere zystennieren e.v.), which is dedicated to adpkd-linked research. this will facilitate recruitment of patients even more. data obtained from the study visits will be collected. the parameters listed below constitute the core data set, additional parameters can be included if considered essential. registered patients will be provided with diaries for the documentation of feeling of hunger, problems and discomforts as well as acetoacetate concentrations in breath. patients are also provided with a portable breath-analyzer to measure acetoacetate concentrations in breath in between study visits. study diaries are collected on visit 4. data capture will be performed at each study visit after enrollment.

Eligibility criteria:
inclusion criteria: * male and female adpkd-patients (diagnosed by genetics / typical mri / ultrasound) * with evidence of fast progression, at least one of the following criteria 1. mayo class 1c-1e 2. truncating pkd1-mutation 3. hypertension \< 35 years 4. urological complications \< 35 years 5. ≥ 1 first class or second class family member with need of renal replacement therapy \< 60 years 6. egfr loss \> 2,5 ml/min/1,73m2 per year 7. propkd-score \> 6 * age ≥ 18 and ≤ 60 years * ckd stage 1-3a according to egfr * signed written informed consent exclusion criteria: * currently under tolvaptan * bmi \ 35 * diabetes mellitus (type i, type ii, mody, lada) * active alcoholism * vegan or vegetarian lifestyle * inability to sign or understand written informed consent * anamnestically known circumstances which forbid the induction of a ketonic state by ketogenic diet or acute fasting (liver damage (ast/alt \> 3x upper limit of normal, alkaline phosphatase \> 6x upper limit of normal , bilirubin ≥ 3 mg/dl), diabetes mellitus, pyruvate carboxylase deficiency, defects of gluconeogenesis, defects of ketolysis / ketogenesis, hyperinsulinism, defects of fatty acid oxidation ) * allergies or food intolerance against components of a ketogenic diet * eating disorders (anorexia nervosa / bulimia) * participation in a weight loss program (e.g. optifast) or intake of medication to promote weight loss within the last six months * ketogenic diet \> 1 month within the last 12 months * chronic renal replacement therapy * previous history of kidney transplantation * uncontrolled local or systemic infection (according to clinical assessment) * simultaneous participation in other interventional studies * pregnant or breastfeeding women * persons who are dependent of or employed by the study investigators * contraindications against mri examinations (stents, pacemakers or other metal inserts, claustrophobia) * persons living in an establishment by court order or official instructions

Keywords: adpkd dietary intervention ketosis fasting ketogenic diet